title: [HER2-positive breast cancer: available targeted agents and biomarkers for therapy response].
abstract: In the last decade, the targeted therapy of breast cancer became part of routine clinical protocols all over the globe. Options in today's targeted therapy include hormonal therapy and the modulation of the EGFR/HER-pathway. Of the four HER receptors, HER2 is the target of currently used treatment strategies. HER2 activates multiple intracellular pathways via RAS, RAF and PI3K. We give a comprehensive summary of approved monoclonal antibodies and tyrosine kinase inhibitors acting over HER2, including trastuzumab, lapatinib and pertuzumab. We elaborate on their mechanism of action and on clinical trials behind their approval. Agents in third phase clinical studies (neratinib, afatinib) are also described. We give a brief overview of agents currently in phase I and phase II studies; these are acting over the PI3K pathway, over IGFR1 and over HSP90. Furthermore, currently validated negative biomarkers (markers predicting lack of response) in clinical use are also summarized. Finally, the major bottlenecks of clinical application including tumor heterogeneity and the high diversity of clinical studies are discussed. For a breakthrough we will need to identify new positive biomarkers of therapy response.
authors.affiliation: Semmelweis Egyetem I. Gyermekklinika, Magyar Tudományos Akadémia Gyermekgyógyászati és Nefrológiai Kutatócsoport, Budapest, Hungary. zsuzsannamihaly@gmail.com.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Mihály
authors.forename: Balázs
authors.initials: B
authors.lastname: Gyõrffy
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000077716:Afatinib; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D002986:Clinical Trials as Topic; D000068338:Everolimus; D005260:Female; D005784:Gene Amplification / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D008453:Maytansine / Q000031:analogs & derivatives / Q000627:therapeutic use; D058990:Molecular Targeted Therapy / Q000379:methods; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000068878:Trastuzumab
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D000077716:Afatinib; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D000068338:Everolimus; D000077341:Lapatinib; D008453:Maytansine; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab; C546842:MTOR protein, human; C508053:ERBB2 protein, human; C487932:neratinib; C485206:pertuzumab